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(1) Background: Optical genome mapping (OGM) is a novel approach to identifying genomic structural variations with high accuracy and resolution. We report a proband with severe short stature caused by 46, XY, der (16) ins (16;15) (q23; q21.3q14) that was detected by OGM combined with other tests and review the clinical features of patients with duplication within 15q14q21.3; (2) Methods: OGM, whole exon sequencing (WES), copy number variation sequencing (CNV-seq), and karyotyping were used; (3) Results: The proband was a 10.7-year-old boy with a complaint of severe short stature (−3.41SDS) and abnormal gait. He had growth hormone deficiency, lumbar lordosis, and epiphyseal dysplasia of both femurs. WES and CNV-seq showed a 17.27 Mb duplication of chromosome 15, and there was an insertion in chromosome 16 found by karyotyping. Furthermore, OGM revealed that duplication of 15q14q21.3 was inversely inserted into 16q23.1, resulting in two fusion genes. A total of fourteen patients carried the duplication of 15q14q21.3, with thirteen previously reported and one from our center, 42.9% of which were de novo. In addition, neurologic symptoms (71.4%,10/14) were the most common phenotypes; (4) Conclusions: OGM combined with other genetic methods can reveal the genetic etiology of patients with the clinical syndrome, presenting great potential for use in properly diagnosing in the genetic cause of the clinical syndrome. [ABSTRACT FROM AUTHOR]

Context: Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy. Objective: This is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response. Patients and Methods: One hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 , and COL11A2. The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized. Results: Twenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which COL2A1 mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include FGFR3 , ACAN , NPR2 , COMP , and FBN1 in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years. Conclusions: A proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required. [ABSTRACT FROM AUTHOR]

Background: 18q- syndrome is a rare chromosomal disease caused by the deletion of the long arm of chromosome 18. Some cases with 18q- syndrome can be combined with growth hormone deficiency (GHD), but data on the efficacy of recombinant human growth hormone (rhGH) treatment in 18q- syndrome are limited. Methods: Here, we report one case of 18q- syndrome successfully treated with long-term rhGH supplement. Previously reported cases in the literature are also reviewed to investigate the karyotype–phenotype relationship and their therapeutic response to rhGH. Results: A 7.9-year-old girl was referred for evaluation for short stature. Physical exam revealed proportionally short stature with a height of 111.10 cm (−3.02 SD score (SDS)), low-set ears, a high-arched palate, a small jaw, webbed neck, widely spaced nipples, long and tapering fingers, and cubitus valgus. Thyroid function test indicated subclinical hypothyroidism. The peak value of growth hormone was 10.26 ng/ml in the levodopa provocation test. Insulin-like growth factor 1 (IGF-1) was 126 ng/ml (57–316 ng/ml). Other laboratory investigations, including complete blood cell count, liver and kidney function, gonadal function, serum adrenocorticotropin levels, and serum cortisol levels, were all within normal ranges. Karyotype analysis showed 46, XX, del (18) (q21). L-Thyroxine replacement and rhGH treatment were initiated and maintained in the following 7 years. At the age of 14.8, her height has reached 159.5 cm with a height SDS increase of 2.82 SDS (from −3.02 SDS to −0.20 SDS). No significant side effects were found during the treatment. The literature review indicated the average rhGH treatment duration of 16 patients was 5.9 ± 3.3 years, and the average height SDS significantly increased from −3.12 ± 0.94 SDS to −1.38 ± 1.29 SDS after the rhGH treatment (p < 0.0001). Conclusion: The main clinical manifestations of 18q- syndrome include characteristic appearance, intellectual disability, and abnormal genital development. The literature review suggested a significant height benefit for short stature with 18q- syndrome from long-term rhGH treatment. [ABSTRACT FROM AUTHOR]

Background: Ring chromosome 15 [r (15)] is an uncommon finding with various clinical manifestations. A common phenotype for these patients has not been established and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with r (15) syndrome are limited. Methods: One short stature patient in our hospital with r (15) syndrome by whole exome sequencing (WES) and karyotype examination was included. All published r (15) syndrome cases as of March 15, 2021, were searched, and their clinical information was recorded and summarized. Results: One 11.5‐year‐old female with prenatal and postnatal growth retardation, ventricular septal defect, intellectual disability, downward corners, short fifth metacarpal bone, scattered milk coffee spots, and a right ovarian cyst was included. Her height was 126.9 cm (−3.45 SDS). Karyotype analysis showed 46, XX, r (15). WES revealed a 4.5 Mb heterozygous deletion in the chromosome 15q26.2‐q26.3 region, encompassing genes from ARRDC4 to OR4F15. Gonadotrophin‐releasing hormone analogue (triptorelin) and rhGH were administered for 6 months. The height has increased 3.8 cm (+0.2SDS) and the calculated growth rate has improved from 4.7 to 7.6 cm/y. The literature review indicated the main clinical manifestations of r (15) syndrome with prenatal and postnatal growth retardation, characteristic craniofacial features, and multisystem abnormalities, and rhGH treatment is beneficial for r (15) syndrome patients with short stature. Conclusion: We delineate the clinical spectrum of r (15) syndrome with the identification of an additional individual and rhGH treatment is beneficial for r (15) syndrome patients with short stature. [ABSTRACT FROM AUTHOR]

Purpose: Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder, and cases caused by variants in SMC3 are infrequent. This article describes a case of CdLS related to a pathogenic variant in SMC3 and performs a literature review. Methods: We collected clinical data and biological samples from a 12-year-old boy with "short stature for 11 years". Gene variants in the proband were detected by whole-exome sequencing, and the variants in his parents were verified by Sanger sequencing. All SMC3 -related CdLS patients from the PubMed and Web of Science databases were collected and summarized using the available data. Results: A pathogenic variant in SMC3 in the proband, c.1942A>G, was identified. Neither of his parents carried the same variant. Twenty-eight patients were diagnosed with CdLS with variants in SMC3 , including the cases in this study and those reported in the literature, where half of the variant types were missense, followed by 32% (9/28) with a deletion and 11% (3/28) with a duplication. All patients showed symptoms of verbal development delay and intellectual disability to different degrees, and 90% patients had long eyelashes while 89% patients had arched eyebrows. Conclusion: This study summarized different gene variants in SMC3 and the frequencies of the various clinical manifestations according to the reported literature. For CdLS caused by SMC3 variants, short stature and facial dysmorphic features are the two most important clinical clues. Definite diagnosis of this rare disease may be challenging clinically; thus, it is significant to use molecular diagnosis. [ABSTRACT FROM AUTHOR]

The objective of the study is to determine the risks and benefits of treating idiopathic short stature (ISS) with aromatase inhibitors (AIs). We comprehensively searched PubMed, Embase, and the China National Knowledge Infrastructure between establishment year and January 31, 2020. Mean difference (MD)/Standardized mean differences (SMD) with 95% confidence intervals (CI) of individual studies were pooled using fixed or random effects models. Subgroup and sensitivity analyses were also performed. Publication bias was estimated using funnel plots and Egger tests. Fourteen studies including 388 participants were included. The meta-analysis results showed that AIs significantly increased final height (MD=2.46, 95% CI: 0.8–4.12) and predicted adult height (MD=0.34, 95% CI: 0.11–0.57). Changes in bone age (MD=–0.1, 95% CI: –0.86–0.66) and bone mineral density (MD=–0.05, 95% CI: –0.19–0.1) were not different between intervention and control group. AI significantly increased testosterone level (SMD=2.01, 95% CI: 0.8–3.23) and reduced estradiol level (SMD=–1.13, 95% CI: –1.87 to –0.40); The intervention and control group had no significant differences in the levels of high-density lipoprotein-cholesterol (SMD=–0.31, 95%CI: –0.68–0.06) and IGF-1 (SMD=0.7, 95% CI: –0.66–2.06) levels. Adverse events were more frequent in the intervention group than in the control group (odds ratio=3.12, 95% CI: 1.44–6.73). In conclusion, both AI monotherapy and AI combination therapy can increase predicted adult height and testosterone levels. [ABSTRACT FROM AUTHOR]

Troyer syndrome is an autosomal recessive disease characterized by spastic paralysis, dysarthria, distal amyotrophy, and short stature. Recently, two siblings (an older brother and a younger sister) were admitted to our hospital for the chief complaints of "short stature and intellectual disability." Through whole exome sequencing of the sister, who is the proband, it was found that her SPG20 gene had compound heterozygous mutations: c.364_365delAT (p.Met122Valfs*2) and c.892delA (p.Thr298Glnfs*30). Target testing revealed that the brother had the same genotype as the sister, and the former mutation originated from the father, while the latter mutation originated from the mother. In summary, this is the first report of Troyer syndrome in a family caused by SPG20 compound heterozygous mutations. A novel SPG20 mutation was found, namely c.892delA (p.Thr298Glnfs*30). In addition, we also summarize these Troyer syndrome patients' heights and their clinical characteristics, and provide a brief review of all known pathogenic mutations of SPG20. [ABSTRACT FROM AUTHOR]

Short stature, skeletal abnormalities, collagenopathies, next-generation sequencing, growth hormone treatment Also, in the B Results b , subsection " I Comparison of Collagen Gene-Related Short Stature With Other Short Stature Genes and Growth Response to rhGH Treatment i ", final paragraph, incorrect height Z scores were presented. Keywords: short stature; skeletal abnormalities; collagenopathies; next-generation sequencing; growth hormone treatment EN short stature skeletal abnormalities collagenopathies next-generation sequencing growth hormone treatment 1 1 1 04/08/22 20220406 NES 220406 In the B Results b , subsection " I Comparison of Collagen Gene-Related Short Stature With Other Short Stature Genes and Growth Response to rhGH Treatment i ", paragraph 2 as published originally, B Table 4 b was incorrectly cited. [Extracted from the article]

Background: Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited developmental disorder with an estimated prevalence of 0.5–10:100,000 and no racial disparity in prevalence. The aim of this study was to present two unrelated Chinese CdLS individuals with mutations in NIPBL and to perform a comprehensive analysis of a Chinese cohort with CdLS. Subjects and methods: Two unrelated Chinese patients complaining of short stature were referred to the outpatient department of Peking Union Medical College Hospital (PUMCH). Their clinical data at birth and at the most recent assessment were collected. Mutation analysis was carried out by whole exome sequencing. Twenty‐four Chinese cases with CdLS were identified through a systematic review of the literature published between 1987 and 2017. Results: Two patients presented with typical phenotypes, characteristic complications of CdLS and mutations in the NIPBL gene. The average age at diagnosis of the 26 Chinese cases was higher than that of other cohorts. The frequencies of characteristic manifestations of CdLS were similar with those of other populations. Conclusions: By investigating 26 Chinese cases of CdLS, we observed that the clinical data and gene variants in the Chinese cohort of CdLS patients were generally in accordance with those of other populations. [ABSTRACT FROM AUTHOR]